Immunological treatment of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Abstract

The present invention relates to an anti-Notch 3 antibody therapy useful for treatment of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. In particular, the invention relates to an anti-Notch3 antibody or a fragment thereof having a 2 fold, 4 fold or 10 fold higher affinity to Notch 3 than to Notch 1 or Notch 2 for use in therapy.

The invention claimed is: 
     
       1. A method of preventing or treating inward remodelling and reduced myogenic tone of brain arteries in a subject in need thereof comprising administering to the subject an effective amount of an anti-Notch3 antibody or a fragment thereof having a 2 fold, 4 fold or 10 fold higher affinity to Notch 3 than to Notch 1 or Notch 2, wherein said anti-Notch3 antibody or fragment thereof binds to an extracellular domain of NOTCH3 (Notch3ECD) deposit and wherein the anti-Notch3 antibody or fragment thereof comprises all of
 a heavy chain variable region H-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; 
 a heavy chain variable region H-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; 
 a heavy chain variable region H-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; 
 a light chain variable region L-CDR1 comprising the amino acid sequence of SEQ ID NO: 12; 
 a light chain variable region L-CDR2 comprising the amino acid sequence of SEQ ID NO: 13; and 
 a light chain variable region L-CDR3 comprising the amino acid sequence of SEQ ID NO: 14. 
 
     
     
       2. The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof does not bind Notch 1 or Notch 2. 
     
     
       3. The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof binds to an epitope comprising amino acids 40-1643 of human Notch3 (SEQ ID NO: 3). 
     
     
       4. The method according to  claim 3  wherein said anti-Notch3 antibody or fragment thereof binds to an epitope comprised in amino acids 657-846 of human Notch3 (SEQ ID NO: 7). 
     
     
       5. The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof is isolated. 
     
     
       6. The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof comprises both a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 15. 
     
     
       7. The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof is humanized. 
     
     
       8. The method according to  claim 1 , wherein the treatment is chronic. 
     
     
       9. The method according to  claim 8 , wherein the chronic treatment is for at least: 2 weeks, 1 month, 6 months, or 1 year. 
     
     
       10. The method of  claim 1 , wherein the subject suffers from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).